Project Summary/Abstract More than 29 million people in the US and 422 million people world-wide are estimated to have diabetes mellitus. Peripheral neuropathy is the most common of the consequences of long term diabetes, affecting more than half of all diabetic patients. Diabetes also impacts the CNS leading to cognitive deficits associated with encephalopathy (loss of neurons) and myelopathy (myelin damage). Diabetes is a risk factor for Alzheimer's disease (AD) and increases risk of progression from mild cognitive impairment to AD. The only current recommendation for preventing or slowing progression of neuropathy is to maintain close glycemic control, which is not feasible for the majority of patients, while there is no recommendation for preventing or slowing encephalopathy. NSI-189 is a new chemical entity that when orally administered promotes endogenous neurogenesis in the adult hippocampus, increases hippocampal volume, enhances synaptic plasticity, and stimulates neuro-regeneration. In our preliminary studies with a mouse model of type 1 diabetes, it has shown the ability to prevent multiple indices of peripheral neuropathy, increase hippocampal volume, and protect long-term memory. In the proposed project, we aim to demonstrate that NSI-189 can prevent and/or reverse peripheral and/or central neuropathy in various animals models of both type 1 and type 2 diabetes.